MRS-7216

Acupuncture is used to manage high blood pressure (BP) in clinical practice. However, the mechanisms underlying its hypotensive effects remain unclear. Our previous studies have shown that electroacupuncture (EA) at the ST36‐37 acupoints, overlying the deep peroneal nerve, attenuates pressor responses through adenosine A2A receptors (A2AR) in the rostral ventrolateral medulla (rVLM). A2AR activation in the rVLM is associated with the upregulation of nitric oxide synthase (NOS) that contributes to sympathoinhibition and BP reduction. However, it is uncertain whether rVLM A2AR contributes to EA’s action in lowering high BP in sustained hypertension (HTN) in the rVLM. We hypothesized that EA lowers BP in HTN through adenosine A2AR mechanisms associated with the upregulation of neuronal NOS (nNOS) in the rVLM. The nNOS derived NO has been shown to exert central effects on BP. To mimic essential HTN in the clinic, we performed EA in conscious Dahl salt‐sensitive hypertensive rat (DSHR). EA (0.1‐0.4 mA, 2 Hz) was applied at ST36‐37 for 30 min twice weekly for four weeks while sham‐EA was conducted with the same procedures as EA except for no electrical stimulation. Elevated BP was reduced by EA (n=10) but not sham‐EA (n=8) and untreated ones (n=6). The A2AR level in the rVLM after EA treatment was increased (n=5; P < 0.05) compared to the sham‐EA (n=5). EA’s inhibitory effect on elevated BP was reversed transiently by unilateral microinjection of SCH 58261 (1 mM in 50 nl; an A2AR antagonist; n=7; P < 0.05) but not the vehicle (n=5) into the rVLM in EA‐treated DSHRs under anesthesia. Activation of rVLM A2AR in DSHRs treated with sham‐EA using an A2AR agonist, CGS‐21680 (0.4 mM in 50 nl; n=6), decreased BP. Furthermore, we found a co‐localization of A2AR with nNOS in the rVLM of DSHRs. The expression of rVLM nNOS was enhanced in DSHRs treated with EA compared to those treated with sham‐EA (n=5 in each group; P < 0.05). These data suggest that adenosine‐ A2AR in the rVLM contributes to EA’s inhibitory effect on elevated BP in sustained HTN, which is likely relevant to the upregulation of nNOS.

Multiple sclerosis (MS) disease activity is associated with blood‐brain barrier (BBB) disruption, which is mediated by inflammatory cytokines released by CD4+ lymphocytes. To assess the effects of adenosine A2A receptors on BBB permeability in vitro and in vivo.

A2A receptor expression was detected by immunostaining in experimental autoimmune encephalomyelitis (EAE) C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG)35–55, and human MS brain. F‐actin and the tight junction protein Claudin‐5 were assessed in endothelial cells treated with an A2A receptor specific agonist (CGS‐21680) after Th1 cytokine stimulation. EAE mice were divided into control and CGS‐21680 (50 µg/kg, i.p., daily) groups. Disease scores were recorded daily to evaluate neurological impairment. The effects of A2A receptor on inflammation and demyelination were assessed after euthanasia by immunostaining or histology; BBB permeability was measured by sodium fluoride (Na‐F) and FITC‐dextran amounts.

Endothelial A2A receptor was detected in demyelination areas of MS brain samples. In EAE lesions, A2A receptor was expressed in the endothelium in association with immune cell infiltration. Treatment with CGS‐21680 counteracted the effects of Th1 cytokines on endothelial cells in vitro, preventing the reduction of tight junction protein expression and stress fiber formation. The effects of A2A receptor activation were correlated with MLCK phosphorylation signaling repression. In EAE, A2A receptor agonist decreased BBB permeability and inhibited EAE neurologic deficiency in mice.

A2A receptor activation at EAE onset helps reduce the effects of Th1 stimulation on BBB permeability, indicating that A2A receptor mediates BBB function in CNS demyelinated disease.